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Addressing the Manufacturing Challenges of Cell-Based Therapies

  • Miguel de Almeida Fuzeta
  • André Dargen de Matos Branco
  • Ana Fernandes-Platzgummer
  • Cláudia Lobato da SilvaEmail author
  • Joaquim M. S. Cabral
Chapter
  • 91 Downloads
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 171)

Abstract

Exciting developments in the cell therapy field over the last decades have led to an increasing number of clinical trials and the first cell products receiving marketing authorization. In spite of substantial progress in the field, manufacturing of cell-based therapies presents multiple challenges that need to be addressed in order to assure the development of safe, efficacious, and cost-effective cell therapies.

The manufacturing process of cell-based therapies generally requires tissue collection, cell isolation, culture and expansion (upstream processing), cell harvest, separation and purification (downstream processing), and, finally, product formulation and storage. Each one of these stages presents significant challenges that have been the focus of study over the years, leading to innovative and groundbreaking technological advances, as discussed throughout this chapter.

Delivery of cell-based therapies relies on defining product targets while controlling process variable impact on cellular features. Moreover, commercial viability is a critical issue that has had damaging consequences for some therapies. Implementation of cost-effectiveness measures facilitates healthy process development, potentially being able to influence end product pricing.

Although cell-based therapies represent a new level in bioprocessing complexity in every manufacturing stage, they also show unprecedented levels of therapeutic potential, already radically changing the landscape of medical care.

Graphical Abstract

Keywords

Bioreactor Cell therapy Hematopoietic stem/progenitor cells (HSPC) Manufacturing Mesenchymal stem/stromal cells (MSC) Process engineering 

References

  1. 1.
    Main JM, Prehn RT (1955) Successful skin homografts after the administration of high dosage x radiation and homologous bone marrow. J Natl Cancer Inst 15:1023–1029PubMedGoogle Scholar
  2. 2.
    Barnes DWH, Corp MJ, Loutit JF, Neal FE (1956) Treatment of murine leukaemia with X rays and homologous bone marrow. Br Med J 2:626–627PubMedPubMedCentralGoogle Scholar
  3. 3.
    Thomas E-D, Lochte HL, Lu WC, Ferreebee JW (1957) Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 257:491–496PubMedGoogle Scholar
  4. 4.
    Gibson T, Medawar PB (1943) The fate of skin homografts in man. J Anat 77:299–310PubMedPubMedCentralGoogle Scholar
  5. 5.
    Billingham RE, Brent L, Medawar PB (1953) ‘Activity acquired tolerance’ of foreign cells. Nature 172:603–606PubMedGoogle Scholar
  6. 6.
    Billingham RE, Brent L (1959) Quantitative studies on tissue transplantation immunity. IV. Induction of tolerance in newborn mice and studies on the phenomenon of runt disease. Philos Trans R Soc Lond B Biol Sci 242:439–477Google Scholar
  7. 7.
    Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561PubMedPubMedCentralGoogle Scholar
  8. 8.
    Dausset J (1958) Iso-Leuco-Anticorps. Acta Haematol 20:156–166PubMedGoogle Scholar
  9. 9.
    Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA (1968) Immunological reconstitution of sex-linked Lymphopenic immunological deficiency. Lancet 2:1366–1369PubMedGoogle Scholar
  10. 10.
    Chabannon C et al (2018) Hematopoietic stem cell transplantation in its 60s – a platform for cellular therapies. Sci Transl Med 10:1–10Google Scholar
  11. 11.
    Kawai T et al (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358:353–361PubMedPubMedCentralGoogle Scholar
  12. 12.
    Gentzkow GD et al (1996) Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 19:350–354PubMedGoogle Scholar
  13. 13.
    Falanga V et al (1998) Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 134:293–300PubMedGoogle Scholar
  14. 14.
    Cuono C, Langdon R, Mcguire J (1986) Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet 327:1123–1124Google Scholar
  15. 15.
    Boyce ST et al (2017) Randomized, paired-site comparison of autologous engineered skin substitutes and split-thickness skin graft for closure of extensive, full-thickness burns. J Burn Care Res 38:61–70PubMedPubMedCentralGoogle Scholar
  16. 16.
    Locatelli F et al (2019) Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130:677–686Google Scholar
  17. 17.
    Brentjens RJ et al (2003) Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and Interleukin-15. Nat Med 9:279–286PubMedGoogle Scholar
  18. 18.
    Kimbrel EA, Lanza R (2015) Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 14:681–692PubMedGoogle Scholar
  19. 19.
    Heathman TR et al (2015) The translation of cell-based therapies: clinical landscape and manufacturing challenges. Regen Med 10:49–64PubMedGoogle Scholar
  20. 20.
    Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650Google Scholar
  21. 21.
    Goujon E (1869) Recherches expérimentales sur les propriétés de la moelle des os. J l’anatomie la Physiol Norm Pathol l’homme des animaux 6:399–412Google Scholar
  22. 22.
    Bianco P, Robey PG, Simmons PJ (2008) Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2:313–319PubMedPubMedCentralGoogle Scholar
  23. 23.
    Tavassoli M, Crosby WH (1968) Transplantation of marrow to extramedullary sites. Science 161:54–56PubMedGoogle Scholar
  24. 24.
    Friedenstein AJ, Chailakhjan RK, Lalykin KS (1970) The development of fibroblast colonies in marrow and spleen cells. Cell Tissue Kinet 3:393–403PubMedGoogle Scholar
  25. 25.
    Friedenstein AJ (1990) Osteogenic stem cells in the bone marrow. In: Bone and mineral research. Elsevier, Amsterdam.  https://doi.org/10.1016/b978-0-444-81371-8.50012-1 CrossRefGoogle Scholar
  26. 26.
    Pittenger MF et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedPubMedCentralGoogle Scholar
  27. 27.
    Horwitz EM et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedGoogle Scholar
  28. 28.
    Dominici M et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317Google Scholar
  29. 29.
    Bourin P et al (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15:641–648PubMedPubMedCentralGoogle Scholar
  30. 30.
    Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98:1076–1084PubMedGoogle Scholar
  31. 31.
    da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 20:419–427Google Scholar
  32. 32.
    Cuende N, Koh MBC, Dominici M, Rasko JEJ, Ikonomou L (2018) Cell, tissue and gene products with marketing authorization in 2018 worldwide. Cytotherapy 20:1401–1413PubMedGoogle Scholar
  33. 33.
    European Medicines Agency. https://www.ema.europa.eu/en. Accessed 20 Mar 2019
  34. 34.
    United States Food and Drug Administration. Approved cellular and gene therapy products. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/default.htm. Accessed 20 Mar 2019
  35. 35.
    Kirouac DC, Zandstra PW (2008) The systematic production of cells for cell therapies. Cell Stem Cell 3:369–381PubMedGoogle Scholar
  36. 36.
    Blasimme A, Rial-Sebbag E (2013) Regulation of cell-based therapies in Europe: current challenges and emerging issues. Stem Cells Dev 22:14–19PubMedPubMedCentralGoogle Scholar
  37. 37.
    Dodson BP, Levine AD (2015) Challenges in the translation and commercialization of cell therapies. BMC Biotechnol 15:1–15Google Scholar
  38. 38.
    Ährlund-Richter L et al (2009) Isolation and production of cells suitable for human therapy: challenges ahead. Cell Stem Cell 4:20–26PubMedGoogle Scholar
  39. 39.
    Lipsitz YY et al (2017) A roadmap for cost-of-goods planning to guide economic production of cell therapy products. Cytotherapy 19:1383–1391PubMedGoogle Scholar
  40. 40.
    Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334PubMedPubMedCentralGoogle Scholar
  41. 41.
    Mueller SM, Glowacki J (2001) Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J Cell Biochem 82:583–590PubMedGoogle Scholar
  42. 42.
    Kern S, Eichler H, Stoeve J, Klüter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301PubMedGoogle Scholar
  43. 43.
    Krause D, Fackler M, Civin C, May W (1996) CD34: structure, biology, and clinical utility. Blood 87:1–13PubMedGoogle Scholar
  44. 44.
    Gallardo D et al (2009) Is mobilized peripheral blood comparable with bone marrow as a source of hematopoietic stem cells for allogeneic transplantation from HLA-identical sibling donors? A case-control study. Haematologica 94:1282–1288PubMedPubMedCentralGoogle Scholar
  45. 45.
    Bashey A et al (2017) Mobilized peripheral blood stem cells versus unstimulated bone marrow as a graft source for T-cell – replete haploidentical donor transplantation using post-transplant cyclophosphamide. J Clin Oncol 35:3002–3009PubMedPubMedCentralGoogle Scholar
  46. 46.
    Oedayrajsingh-Varma MJ et al (2006) Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 8:166–177PubMedGoogle Scholar
  47. 47.
    Rubinstein P et al (1995) Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci U S A 92:10119–10122PubMedPubMedCentralGoogle Scholar
  48. 48.
    Wyrsch A et al (1999) Umbilical cord blood from preterm human fetuses is rich in committed and primitive hematopoietic progenitors with high proliferative and self-renewal capacity. Exp Hematol 27:1338–1345PubMedGoogle Scholar
  49. 49.
    Prindull G et al (1987) CFU-F circulating in cord blood. Blut 54:351–359PubMedGoogle Scholar
  50. 50.
    Mennan C et al (2016) Mesenchymal stromal cells derived from whole human umbilical cord exhibit similar properties to those derived from Wharton’s jelly and bone marrow. FEBS Open Bio 6:1054–1066PubMedPubMedCentralGoogle Scholar
  51. 51.
    Barker JN et al (2019) CD34+ cell content of 126 341 cord blood units in the US inventory: implications for transplantation and banking. Blood Adv 3:1267–1271PubMedPubMedCentralGoogle Scholar
  52. 52.
    Troyer DL, Weiss ML (2008) Concise review: Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 26:591–599PubMedGoogle Scholar
  53. 53.
    Goodwin HS et al (2001) Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat, and neural markers. Biol Blood Marrow Transplant 7:581–588PubMedGoogle Scholar
  54. 54.
    Wang JC, Doedens M, Dick JE (1997) Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood 89:3919–3924PubMedGoogle Scholar
  55. 55.
    De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP (2001) Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 44:1928–1942PubMedGoogle Scholar
  56. 56.
    Fukuchi Y et al (2004) Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 22:649–658PubMedGoogle Scholar
  57. 57.
    Karaöz E et al (2010) Isolation and in vitro characterisation of dental pulp stem cells from natal teeth. Histochem Cell Biol 133:95–112PubMedGoogle Scholar
  58. 58.
    da Silva Meirelles L, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213PubMedGoogle Scholar
  59. 59.
    Ribeiro A et al (2013) Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther 4:125PubMedPubMedCentralGoogle Scholar
  60. 60.
    Vormittag P, Gunn R, Ghorashian S, Veraitch FS (2018) A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol 53:164–181PubMedGoogle Scholar
  61. 61.
    Lennon DP, Caplan AI (2006) Isolation of rat marrow-derived mesenchymal stem cells. Exp Hematol 34:1606–1607PubMedGoogle Scholar
  62. 62.
    Lu LL et al (2006) Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 91:1017–1026PubMedGoogle Scholar
  63. 63.
    Nimura A et al (2008) Increased proliferation of human synovial mesenchymal stem cells with autologous human serum: comparisons with bone marrow mesenchymal stem cells and with fetal bovine serum. Arthritis Rheum 58:501–510PubMedGoogle Scholar
  64. 64.
    De Bruyn C et al (2010) A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton’s jelly without enzymatic treatment. Stem Cells Dev 20:547–557PubMedGoogle Scholar
  65. 65.
    Ghorbani A, Jalali SA, Varedi M (2014) Isolation of adipose tissue mesenchymal stem cells without tissue destruction: a non-enzymatic method. Tissue Cell 46:54–58PubMedGoogle Scholar
  66. 66.
    Zhang S, Muneta T, Morito T, Mochizuki T, Sekiya I (2008) Autologous synovial fluid enhances migration of mesenchymal stem cells from synovium of osteoarthritis patients in tissue culture system. J Orthop Res 26:1413–1418PubMedGoogle Scholar
  67. 67.
    Aktas M, Radke TF, Strauer BE, Wernet P, Kogler G (2008) Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax. Cytotherapy 10:203–211PubMedGoogle Scholar
  68. 68.
    Eyrich M et al (2014) Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells. Cytotherapy 16:946–964PubMedGoogle Scholar
  69. 69.
    Stroncek DF et al (2014) Counter-flow elutriation of clinical peripheral blood mononuclear cell concentrates for the production of dendritic and T cell therapies. J Transl Med 12:241PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kato K, Radbruch A (1993) Isolation and characterization of CD34+ hematopoietic stem cells from human peripheral blood by high-gradient magnetic cell sorting. Cytometry 14:384–392PubMedGoogle Scholar
  71. 71.
    De Wynter EA et al (1995) Comparison of purity and enrichment of CD34+ cells from bone marrow, umbilical cord and peripheral blood (primed for apheresis) using five separation systems. Stem Cells 13:524–532PubMedGoogle Scholar
  72. 72.
    Simmons PJ, Torok-Storb B (1991) Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 78:55–62Google Scholar
  73. 73.
    Gonçalves R, da Silva CL, Cabral JMS, Zanjani ED, Almeida-Porada G (2006) A Stro-1+ human universal stromal feeder layer to expand/maintain human bone marrow hematopoietic stem/progenitor cells in a serum-free culture system. Exp Hematol 34:1353–1359PubMedGoogle Scholar
  74. 74.
    Leong W, Nankervis B, Beltzer J (2019) Automation: what will the cell therapy laboratory of the future look like? Cell Gene Ther Insights 4:679–694Google Scholar
  75. 75.
    Sutermaster BA, Darling EM (2019) Considerations for high-yield, high-throughput cell enrichment: fluorescence versus magnetic sorting. Sci Rep 9:1–9Google Scholar
  76. 76.
    Koehl U et al (2004) IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation. Blood Cells Mol Dis 33:261–266PubMedGoogle Scholar
  77. 77.
    Neurauter AA et al (2007) Cell isolation and expansion using dynabeads. Adv Biochem Eng Biotechnol 106:41–73PubMedGoogle Scholar
  78. 78.
    Rogers S, Pritchard R, Zhukov A (2018) A faster GMP therapeutic cell sorter enabled by a new microfluidic technology: the inertial vortex sorter. Cytotherapy 20:S70Google Scholar
  79. 79.
    Feng X et al (2010) Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development. Blood 115:510–518PubMedPubMedCentralGoogle Scholar
  80. 80.
    Kokaji AI (2018) Method for the in situ formation of bifunctional immunological complexes. US 2018/0188245A1Google Scholar
  81. 81.
    Dai X, Mei Y, Nie J, Bai Z (2019) Scaling up the manufacturing process of adoptive T cell immunotherapy. Biotechnol J 14:1800239Google Scholar
  82. 82.
    McNaughton BH, Younger JG, Ostruszka LJ (2019) Method and system for buoyant separation. US 10,195,547 B2Google Scholar
  83. 83.
    Liou Y-R, Wang Y-H, Lee C-Y, Li P-C (2015) Buoyancy-activated cell sorting using targeted biotinylated albumin microbubbles. PLoS One 10:e0125036PubMedPubMedCentralGoogle Scholar
  84. 84.
    Aijaz A et al (2018) Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng 2:362–376PubMedPubMedCentralGoogle Scholar
  85. 85.
    Burgener A, Butler M (2005) Medium development. In: Ozturck SS, Hu WS (eds) Cell culture technology for pharmaceutical and cell-based therapies. CRC Press, Boca Raton, pp 41–64Google Scholar
  86. 86.
    Yao T, Asayama Y (2017) Animal-cell culture media: history, characteristics, and current issues. Reprod Med Biol 16:99–117PubMedPubMedCentralGoogle Scholar
  87. 87.
    de Lima M et al (2012) Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med 367:2305–2315PubMedPubMedCentralGoogle Scholar
  88. 88.
    Horwitz ME et al (2019) Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol 37:367–374PubMedGoogle Scholar
  89. 89.
    Wagner JE et al (2016) Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 18:144–155PubMedGoogle Scholar
  90. 90.
    Brunner D, Appl H, Pfaller W, Gstraunthaler G (2010) Serum-free cell culture: the serum-free media interactive online database. ALTEX 27:53–62PubMedGoogle Scholar
  91. 91.
    Spees JL et al (2004) Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther 9:747–756PubMedGoogle Scholar
  92. 92.
    European Medicines Agency (2007) Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006). Off J Eur UnionGoogle Scholar
  93. 93.
    European Medicines Agency (2011) Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01 rev.3). Off J Eur UnionGoogle Scholar
  94. 94.
    US Food and Drug Administration (2019) Medical devices containing materials derived from animal sources (except for in vitro diagnostic devices)Google Scholar
  95. 95.
    Karnieli O et al (2017) A consensus introduction to serum replacements and serum-free media for cellular therapies. Cytotherapy 19:155–169PubMedGoogle Scholar
  96. 96.
    Hara Y, Steiner M, Baldini MG (1980) Platelets as a source of growth-Dromotina factor(s) for tumor cells. Cancer Res 40:1212–1216PubMedGoogle Scholar
  97. 97.
    Umeno Y, Okuda A, Kimura G (1989) Proliferative behaviour of fibroblasts in plasma-rich culture medium. J Cell Sci 94:567–575PubMedGoogle Scholar
  98. 98.
    Burnouf T, Strunk D, Koh MBC, Schallmoser K (2016) Human platelet lysate: replacing fetal bovine serum as a gold standard for human cell propagation? Biomaterials 76:371–387PubMedGoogle Scholar
  99. 99.
    van der Valk J et al (2018) Fetal bovine serum (FBS): past–present–future. ALTEX 35:99–118PubMedGoogle Scholar
  100. 100.
    Doucet C et al (2005) Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. J Cell Physiol 205:228–236PubMedGoogle Scholar
  101. 101.
    Reinisch A et al (2015) Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation. Blood 125:249–260PubMedPubMedCentralGoogle Scholar
  102. 102.
    Kinzebach S, Dietz L, Klüter H, Thierse HJ, Bieback K (2013) Functional and differential proteomic analyses to identify platelet derived factors affecting ex vivo expansion of mesenchymal stromal cells. BMC Cell Biol 14:48PubMedPubMedCentralGoogle Scholar
  103. 103.
    de Soure AM et al (2017) Integrated culture platform based on a human platelet lysate supplement for the isolation and scalable manufacturing of umbilical cord matrix-derived mesenchymal stem/stromal cells. J Tissue Eng Regen Med 11:1630–1640PubMedGoogle Scholar
  104. 104.
    Sousa Pinto D et al (2019) Scalable manufacturing of human mesenchymal stromal cells in the Vertical-Wheel™ bioreactor system: an experimental and economic approach. Biotechnol J:1800716.  https://doi.org/10.1002/biot.201800716 Google Scholar
  105. 105.
    Schallmoser K et al (2007) Human platelet lysate can replace fetal bovine serum for clinical-scale expansion of functional mesenchymal stromal cells. Transfusion 47:1436–1446PubMedGoogle Scholar
  106. 106.
    Atashi F, Jaconi MEE, Pittet-Cuénod B, Modarressi A (2014) Autologous platelet-rich plasma: a biological supplement to enhance adipose-derived mesenchymal stem cell expansion. Tissue Eng Part C Methods 21:253–262PubMedPubMedCentralGoogle Scholar
  107. 107.
    Naveau A et al (2010) Phenotypic study of human gingival fibroblasts in a medium enriched with platelet lysate. J Periodontol 82:632–641PubMedGoogle Scholar
  108. 108.
    Hildner F et al (2015) Human platelet lysate successfully promotes proliferation and subsequent chondrogenic differentiation of adipose-derived stem cells: a comparison with articular chondrocytes. J Tissue Eng Regen Med 9:808–818PubMedGoogle Scholar
  109. 109.
    Mazzocca AD et al (2012) The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells. Am J Sports Med 40:1742–1749PubMedGoogle Scholar
  110. 110.
    Hofbauer P et al (2014) Human platelet lysate is a feasible candidate to replace fetal calf serum as medium supplement for blood vascular and lymphatic endothelial cells. Cytotherapy 16:1238–1244PubMedGoogle Scholar
  111. 111.
    Hemeda H, Giebel B, Wagner W (2014) Evaluation of human platelet lysate versus fetal bovine serum for culture of mesenchymal stromal cells. Cytotherapy 16:170–180PubMedGoogle Scholar
  112. 112.
    Huang C et al (2019) Gamma irradiation of human platelet lysate: validation of efficacy for pathogen reduction and assessment of impacts on HPL performance. Cytotherapy 21:S82–S83Google Scholar
  113. 113.
    Simões IN et al (2013) Human mesenchymal stem cells from the umbilical cord matrix: successful isolation and ex vivo expansion using serum−/xeno-free culture media. Biotechnol J 8:448–458PubMedGoogle Scholar
  114. 114.
    Carmelo JG, Fernandes-Platzgummer A, Diogo MM, da Silva CL, Cabral JMS (2015) A xeno-free microcarrier-based stirred culture system for the scalable expansion of human mesenchymal stem/stromal cells isolated from bone marrow and adipose tissue. Biotechnol J 10:1235–1247PubMedGoogle Scholar
  115. 115.
    Al-Saqi SH et al (2014) Defined serum-free media for in vitro expansion of adipose-derived mesenchymal stem cells. Cytotherapy 16:915–926PubMedGoogle Scholar
  116. 116.
    Chen G et al (2014) Human umbilical cord-derived mesenchymal stem cells do not undergo malignant transformation during long-term culturing in serum-free medium. PLoS One 9:1–8Google Scholar
  117. 117.
    Spanholtz J et al (2010) High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS One 5:e9221PubMedPubMedCentralGoogle Scholar
  118. 118.
    Wang Y et al (2014) Human mesenchymal stem cells possess different biological characteristics but do not change their therapeutic potential when cultured in serum free medium. Stem Cell Res Ther 5:1–14Google Scholar
  119. 119.
    Smith C et al (2015) Ex vivo expansion of human T cells for adoptive immunotherapy using the novel xeno-free CTS immune cell serum replacement. Clin Transl Immunol 4:e31Google Scholar
  120. 120.
    Lu TL et al (2016) A rapid cell expansion process for production of engineered autologous CAR-T cell therapies. Hum Gene Ther Methods 27:209–218PubMedPubMedCentralGoogle Scholar
  121. 121.
    Fliefel R et al (2016) Mesenchymal stem cell proliferation and mineralization but not osteogenic differentiation are strongly affected by extracellular pH. J Cranio-Maxillofac Surg 44:715–724Google Scholar
  122. 122.
    Mcadams TA, Miller WM, Papoutsakis ET (1997) Variations in culture pH affect the cloning efficiency and differentiation of progenitor cells in ex vivo haemopoiesis. Br J Haematol 97:889–895PubMedGoogle Scholar
  123. 123.
    Stolzing A, Scutt A (2006) Effect of reduced culture temperature on antioxidant defences of mesenchymal stem cells. Free Radic Biol Med 41:326–338PubMedGoogle Scholar
  124. 124.
    Waymouth C (1970) Osmolality of mammalian blood and of media for. In Vitro 6:109–110PubMedGoogle Scholar
  125. 125.
    Mather JP, Roberts PE (1998) Introduction to cell and tissue culture: theory and technique. Plenum Press, New YorkGoogle Scholar
  126. 126.
    Eliasson P, Jönsson JI (2010) The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol 222:17–22PubMedGoogle Scholar
  127. 127.
    Spencer JA et al (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–273PubMedPubMedCentralGoogle Scholar
  128. 128.
    Valorani MG et al (2012) Pre-culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials. Cell Prolif 45:225–238PubMedGoogle Scholar
  129. 129.
    Dos Santos F et al (2010) Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. J Cell Physiol 223:27–35PubMedGoogle Scholar
  130. 130.
    Lee HH et al (2013) Hypoxia enhances chondrogenesis and prevents terminal differentiation through PI3K/Akt/FoxO dependent anti-apoptotic effect. Sci Rep 3:1–12Google Scholar
  131. 131.
    Oliveira PH et al (2012) Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells. Stem Cell Res 9:225–236PubMedGoogle Scholar
  132. 132.
    Roy S, Tripathy M, Mathur N, Jain A, Mukhopadhyay A (2012) Hypoxia improves expansion potential of human cord blood-derived hematopoietic stem cells and marrow repopulation efficiency. Eur J Haematol 88:396–405PubMedGoogle Scholar
  133. 133.
    Andrade PZ et al (2015) Ex vivo expansion of cord blood haematopoietic stem/progenitor cells under physiological oxygen tensions: clear-cut effects on cell proliferation, differentiation and metabolism. J Tissue Eng Regen Med 9:1172–1181PubMedGoogle Scholar
  134. 134.
    Guruvenket S, Rao GM, Komath M, Raichur AM (2004) Plasma surface modification of polystyrene and polyethylene. Appl Surf Sci 236:278–284Google Scholar
  135. 135.
    Jung S, Sen A, Rosenberg L, Behie LA (2010) Identification of growth and attachment factors for the serum-free isolation and expansion of human mesenchymal stromal cells. Cytotherapy 12:637–657PubMedGoogle Scholar
  136. 136.
    Bryhan MD, Gagnon PE, LaChance OV, Shen Z-H, Wang H (2003) Method for creating a cell growth surface on a polymeric substrate. US 6,617,152 B2Google Scholar
  137. 137.
    Swistowski A et al (2009) Xeno-free defined conditions for culture of human embryonic stem cells, neural stem cells and dopaminergic neurons derived from them. PLoS One 4:e6233PubMedPubMedCentralGoogle Scholar
  138. 138.
    Lee DW et al (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517–528PubMedPubMedCentralGoogle Scholar
  139. 139.
    Saint-Jean M et al (2018) Adoptive cell therapy with tumor-infiltrating lymphocytes in advanced melanoma patients. J Immunol Res 2018:3530148PubMedPubMedCentralGoogle Scholar
  140. 140.
    Pardo AMP, Rothenberg ME (2013) Large scale expansion of human mesenchymal stem cells using Corning® stemgro® hMSC Medium and Corning CellBIND ® Surface HYPER Stack® cell culture vessels. Corning, TewksburyGoogle Scholar
  141. 141.
    Blasey HD, Isch C, Bernard AR (1995) Cellcube: a new system for large scale growth of adherent cells. Biotechnol Tech 9:725–728Google Scholar
  142. 142.
    Lambrechts T et al (2016) Evaluation of a monitored multiplate bioreactor for large-scale expansion of human periosteum derived stem cells for bone tissue engineering applications. Biochem Eng J 108:58–68Google Scholar
  143. 143.
    Andrade-Zaldivar H, Kalixto-Sánchez MA, Barba de la Rosa AP, León-Rodriguez A (2011) Expansion of human hematopoietic cells from umbilical cord blood using roller bottles in CO2 and CO2-free atmosphere. Stem Cells Dev 20:593–598PubMedGoogle Scholar
  144. 144.
    Wikström K, Blomberg P, Islam KB (2004) Clinical grade vector production: analysis of yield, stability, and storage of GMP-produced retroviral vectors for gene therapy. Biotechnol Prog 20:1198–1203PubMedGoogle Scholar
  145. 145.
    Wang H, Kehoe D, Murrell J, Jing D (2017) Structured methodology for process development in scalable stirred tank bioreactors platforms. In: Connon CJ (ed) Bioprocessing for cell-based therapies. Wiley, Hoboken, pp 35–64Google Scholar
  146. 146.
    Bayley R et al (2018) The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors. J Tissue Eng Regen Med 12:e368–e378PubMedGoogle Scholar
  147. 147.
    Martin Y, Eldardiri M, Lawrence-Watt DJ, Sharpe JR (2010) Microcarriers and their potential in tissue regeneration. Tissue Eng Part B Rev 17:71–80PubMedGoogle Scholar
  148. 148.
    Chen AKL, Reuveny S, Oh SKW (2013) Application of human mesenchymal and pluripotent stem cell microcarrier cultures in cellular therapy: achievements and future direction. Biotechnol Adv 31:1032–1046PubMedGoogle Scholar
  149. 149.
    dos Santos F et al (2014) A xenogeneic-free bioreactor system for the clinical-scale expansion of human mesenchymal stem/stromal cells. Biotechnol Bioeng 116:1116–1127Google Scholar
  150. 150.
    Mizukami A et al (2016) Stirred tank bioreactor culture combined with serum-/xenogeneic-free culture medium enables an efficient expansion of umbilical cord-derived mesenchymal stem/stromal cells. Biotechnol J 11:1048–1059PubMedGoogle Scholar
  151. 151.
    Rafiq QA, Brosnan KM, Coopman K, Nienow AW, Hewitt CJ (2013) Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor. Biotechnol Lett 35:1233–1245PubMedGoogle Scholar
  152. 152.
    Lawson T et al (2017) Process development for expansion of human mesenchymal stromal cells in a 50L single-use stirred tank bioreactor. Biochem Eng J 120:49–62Google Scholar
  153. 153.
    Schirmaier C et al (2014) Scale-up of adipose tissue-derived mesenchymal stem cell production in stirred single-use bioreactors under low-serum conditions. Eng Life Sci 14:292–303Google Scholar
  154. 154.
    Robb KP, Fitzgerald JC, Barry F, Viswanathan S (2019) Mesenchymal stromal cell therapy: progress in manufacturing and assessments of potency. Cytotherapy 21:289–306PubMedGoogle Scholar
  155. 155.
    Tsai AC, Liu Y, Ma T (2016) Expansion of human mesenchymal stem cells in fibrous bed bioreactor. Biochem Eng J 108:51–57Google Scholar
  156. 156.
    Haack-Sørensen M et al (2016) Culture expansion of adipose derived stromal cells. A closed automated Quantum Cell Expansion System compared with manual flask-based culture. J Transl Med 14:319PubMedPubMedCentralGoogle Scholar
  157. 157.
    Mizukami A et al (2018) A fully-closed and automated hollow fiber bioreactor for clinical-grade manufacturing of human mesenchymal stem/stromal cells. Stem Cell Rev Rep 14:141–143PubMedGoogle Scholar
  158. 158.
    Tirughana R et al (2018) GMP production and scale-up of adherent neural stem cells with a quantum cell expansion system. Mol Ther Methods Clin Dev 10:48–56PubMedPubMedCentralGoogle Scholar
  159. 159.
    Lechanteur C et al (2014) Large-scale clinical expansion of mesenchymal stem cells in the GMP-compliant, closed automated Quantum® Cell Expansion System: comparison with expansion in traditional T-flasks. J Stem Cell Res Ther 4:1000222Google Scholar
  160. 160.
    Lambrechts T et al (2016) Large-scale progenitor cell expansion for multiple donors in a monitored hollow fibre bioreactor. Cytotherapy 18:1219–1233PubMedGoogle Scholar
  161. 161.
    Junne S, Neubauer P (2018) How scalable and suitable are single-use bioreactors? Curr Opin Biotechnol 53:240–247PubMedGoogle Scholar
  162. 162.
    Doran PM (2013) Bioprocess engineering principles. Academic, LondonGoogle Scholar
  163. 163.
    Schürch U, Kramer H, Einsele A, Widmer F, Eppenberger HM (1988) Experimental evaluation of laminar shear stress on the behaviour of hybridoma mass cell cultures, producing monoclonal antibodies against mitochondrial creatine kinase. J Biotechnol 7:179–184Google Scholar
  164. 164.
    McQueen A, Bailey JE (1989) Influence of serum level, cell line, flow type and viscosity on flow-induced lysis of suspended mammalian cells. Biotechnol Lett 11:531–536Google Scholar
  165. 165.
    Chisti Y (2001) Hydrodynamic damage to animal cells. Crit Rev Biotechnol 21:67–110PubMedPubMedCentralGoogle Scholar
  166. 166.
    McDowell CL, Papoutsakis ET (1998) Increased agitation intensity increases CD13 receptor surface content and mRNA levels, and alters the metabolism of HL60 cells cultured in stirred tank bioreactors. Biotechnol Bioeng 60:239–250PubMedGoogle Scholar
  167. 167.
    Jing Q, Cai H, Du Z, Ye Z, Tan WS (2013) Effects of agitation speed on the ex vivo expansion of cord blood hematopoietic stem/progenitor cells in stirred suspension culture. Artif Cells Nanomed Biotechnol 41:98–102PubMedGoogle Scholar
  168. 168.
    Yourek G, McCormick SM, Mao JJ, Reilly GC (2010) Shear stress induces osteogenic differentiation of human mesenchymal stem cells. Regen Med 5:713–724PubMedPubMedCentralGoogle Scholar
  169. 169.
    Hu K, Sun H, Gui B, Sui C (2017) TRPV4 functions in flow shear stress induced early osteogenic differentiation of human bone marrow mesenchymal stem cells. Biomed Pharmacother 91:841–848PubMedGoogle Scholar
  170. 170.
    Bassaneze V et al (2009) Shear stress induces nitric oxide–mediated vascular endothelial growth factor production in human adipose tissue mesenchymal stem cells. Stem Cells Dev 19:371–378Google Scholar
  171. 171.
    Öncul AA, Kalmbach A, Genzel Y, Reichl U, Thévenin D (2010) Characterization of flow conditions in 2 L and 20 L wave bioreactors® using computational fluid dynamics. Biotechnol Prog 26:101–110PubMedGoogle Scholar
  172. 172.
    Timmins NE et al (2009) Clinical scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells. Biotechnol Bioeng 104:832–840PubMedGoogle Scholar
  173. 173.
    Sutlu T et al (2010) Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor. Cytotherapy 12:1044–1055PubMedGoogle Scholar
  174. 174.
    Croughan MS, Giroux D, Fang D, Lee B (2016) Novel single-use bioreactors for scale-up of anchorage-dependent cell manufacturing for cell therapies. In: Cabral JMS, da Silva CL, Chase LG, Diogo MM (eds) Stem cell manufacturing. Elsevier, Amsterdam, pp 105–139.  https://doi.org/10.1016/B978-0-444-63265-4.00005-4 CrossRefGoogle Scholar
  175. 175.
    Sousa MFQ et al (2015) Production of oncolytic adenovirus and human mesenchymal stem cells in a single-use, Vertical-Wheel bioreactor system: impact of bioreactor design on performance of microcarrier-based cell culture processes. Biotechnol Prog 31:1600–1612PubMedGoogle Scholar
  176. 176.
    Rodrigues CAV et al (2018) Scalable culture of human induced pluripotent cells on microcarriers under xeno-free conditions using single-use Vertical-Wheel™ bioreactors. J Chem Technol Biotechnol 93:3597–3606Google Scholar
  177. 177.
    Campbell A et al (2015) Concise review: process development considerations for cell therapy. Stem Cells Transl Med 4:1155–1163PubMedPubMedCentralGoogle Scholar
  178. 178.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2004) Guidance for Industry: PAT, a framework for innovative pharmaceutical development, manufacturing, and quality assurance. WashingtonGoogle Scholar
  179. 179.
    EMEA (2006) Mandate for Process Analytical Technology Team (EMEA/48327/2006 Mandate). European Medicines AgencyGoogle Scholar
  180. 180.
    Claßen J, Aupert F, Reardon KF, Solle D, Scheper T (2017) Spectroscopic sensors for in-line bioprocess monitoring in research and pharmaceutical industrial application. Anal Bioanal Chem 409:651–666PubMedGoogle Scholar
  181. 181.
    Biechele P, Busse C, Solle D, Scheper T, Reardon K (2015) Sensor systems for bioprocess monitoring. Eng Life Sci 15:469–488Google Scholar
  182. 182.
    O’Mara P, Farrell A, Bones J, Twomey K (2018) Staying alive! Sensors used for monitoring cell health in bioreactors. Talanta 176:130–139PubMedGoogle Scholar
  183. 183.
    Haber F, Hlemensiewicz Z (1909) Über elektrische Phasengrenzkräfte. Z Phys Chem 67U:385–431Google Scholar
  184. 184.
    Clark LC, Wolf R, Granger D, Taylor Z (1953) Continuous recording of blood oxygen tensions by polarography. J Appl Physiol 6:189–193PubMedGoogle Scholar
  185. 185.
    Jeevarajan AS, Vani S, Taylor TD, Anderson MM (2002) Continuous pH monitoring in a perfused bioreactor system using an optical pH sensor. Biotechnol Bioeng 78:467–472PubMedGoogle Scholar
  186. 186.
    Ge X et al (2006) Validation of an optical sensor-based high-throughput bioreactor system for mammalian cell culture. J Biotechnol 122:293–306PubMedGoogle Scholar
  187. 187.
    Hanson MA et al (2007) Comparisons of optical pH and dissolved oxygen sensors with traditional electrochemical probes during mammalian cell culture. Biotechnol Bioeng 97:833–841PubMedGoogle Scholar
  188. 188.
    Ude C et al (2014) Application of an online-biomass sensor in an optical multisensory platform prototype for growth monitoring of biotechnical relevant microorganism and cell lines in single-use shake flasks. Sensors (Basel) 14:17390–17405Google Scholar
  189. 189.
    Lavine BK (2000) Chemometrics. Anal Chem 72:91–98Google Scholar
  190. 190.
    Arnold SA, Crowley J, Woods N, Harvey LM, McNeil B (2003) In-situ near infrared spectroscopy to monitor key analytes in mammalian cell cultivation. Biotechnol Bioeng 84:13–19PubMedGoogle Scholar
  191. 191.
    Salasznyk RM, Klees RF, Williams WA, Boskey A, Plopper GE (2007) Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells. Exp Cell Res 313:22–37PubMedGoogle Scholar
  192. 192.
    Rosa F et al (2016) Monitoring the ex-vivo expansion of human mesenchymal stem/stromal cells in xeno-free microcarrier-based reactor systems by MIR spectroscopy. Biotechnol Prog 32:447–455PubMedGoogle Scholar
  193. 193.
    Suhito IR, Han Y, Min J, Son H, Kim TH (2018) In situ label-free monitoring of human adipose-derived mesenchymal stem cell differentiation into multiple lineages. Biomaterials 154:223–233PubMedGoogle Scholar
  194. 194.
    Gomes J, Chopda V, Rathore AS (2018) Monitoring and control of bioreactor: basic concepts and recent advances. In: Bioprocessing technology for production of biopharmaceuticals and bioproducts. Wiley, Hoboken, pp 201–237.  https://doi.org/10.1002/9781119378341.ch6 CrossRefGoogle Scholar
  195. 195.
    Mercier SM et al (2016) Process analytical technology tools for perfusion cell culture. Eng Life Sci 16:25–35Google Scholar
  196. 196.
    Courtès F, Ebel B, Guédon E, Marc A (2016) A dual near-infrared and dielectric spectroscopies strategy to monitor populations of Chinese hamster ovary cells in bioreactor. Biotechnol Lett 38:745–750PubMedGoogle Scholar
  197. 197.
    Horiguchi I, Sakai Y (2016) Serum replacement with albumin-associated lipids prevents excess aggregation and enhances growth of induced pluripotent stem cells in suspension culture. Biotechnol Prog 32:1009–1016PubMedGoogle Scholar
  198. 198.
    Dekker L, Polizzi KM (2017) Sense and sensitivity in bioprocessing – detecting cellular metabolites with biosensors. Curr Opin Chem Biol 40:31–36PubMedGoogle Scholar
  199. 199.
    Baradez M-O, Biziato D, Hassan E, Marshall D (2018) Application of Raman spectroscopy and univariate modelling as a process analytical technology for cell therapy bioprocessing. Front Med 5:47Google Scholar
  200. 200.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedGoogle Scholar
  201. 201.
    Lei Y, Schaffer DV (2013) A fully defined and scalable 3D culture system for human pluripotent stem cell expansion and differentiation. Proc Natl Acad Sci U S A 110:E5039–E5048PubMedPubMedCentralGoogle Scholar
  202. 202.
    dos Santos F et al (2014) A xenogeneic-free bioreactor system for the clinical-scale expansion of human mesenchymal stem/stromal cells. Biotechnol Bioeng 111:1116–1127PubMedGoogle Scholar
  203. 203.
    Mariappan I et al (2010) In vitro culture and expansion of human limbal epithelial cells. Nat Protoc 5:1470–1479PubMedGoogle Scholar
  204. 204.
    Joen VT, Declercq H, Cornelissen M (2011) Expansion of human embryonic stem cells: a comparative study. Cell Prolif 44:462–476Google Scholar
  205. 205.
    Rowley J, Abraham E, Campbell A, Brandwein H, Oh S (2012) Meeting lot-size challenges of manufacturing adherent cells for therapy. Bioprocess Int 10:16–22Google Scholar
  206. 206.
    Rodrigues AL et al (2019) Dissolvable microcarriers allow scalable expansion and harvesting of human induced pluripotent stem cells under xeno-free conditions. Biotechnol J 14:1800461Google Scholar
  207. 207.
    Zhang J et al (2015) Thermo-responsive microcarriers based on poly (N-isopropylacrylamide). Eur Polym J 67:346–364Google Scholar
  208. 208.
    Nguyen LTB, Odeleye AOO, Chui CY, Baudequin T (2019) Development of thermo-responsive polycaprolactone macrocarriers conjugated with poly (N-isopropyl acrylamide) for cell culture. Sci Rep 9:1–11Google Scholar
  209. 209.
    Cunha B et al (2015) Filtration methodologies for the clarification and concentration of human mesenchymal stem cells. J Membr Sci 478:117–129Google Scholar
  210. 210.
    Schnitzler AC et al (2016) Bioprocessing of human mesenchymal stem/stromal cells for therapeutic use: current technologies and challenges. Biochem Eng J 108:3–13Google Scholar
  211. 211.
    Mehta S, Herman T, Ross H, Iqbal K, McMahon J (2016) Methods and systems for manipulating particles using a fluidized bed. US 9,279,133 B2Google Scholar
  212. 212.
    Cunha B et al (2015) Exploring continuous and integrated strategies for the up- and downstream processing of human mesenchymal stem cells. J Biotechnol 213:97–108PubMedGoogle Scholar
  213. 213.
    Wang Z, Feke D, Belovich J (2014) Acoustic device and methods thereof for separation and concentration. US 8,889,388 B2Google Scholar
  214. 214.
    Woods EJ, Thirumala S, Badhe-buchanan SS, Clarke D, Mathew ABYJ (2016) Off the shelf cellular therapeutics: factors to consider during cryopreservation and storage of human cells for clinical use. Cytotherapy 18:697–711PubMedGoogle Scholar
  215. 215.
    Lee S et al (2008) Post-thaw viable CD34+ cell count is a valuable predictor of haematopoietic stem cell engraftment in autologous peripheral blood stem cell transplantation. Vox Sang 94:146–152PubMedGoogle Scholar
  216. 216.
    Allan DS et al (2002) Number of viable CD34+ cells reinfused predicts engraftment in autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 29:967–972PubMedGoogle Scholar
  217. 217.
    Chatzistamatiou TK et al (2014) Optimizing isolation culture and freezing methods to preserve Wharton’s jelly’s mesenchymal stem cell (MSC) properties: an MSC banking protocol validation for the Hellenic Cord Blood Bank. Transfusion 54:3108–3120PubMedGoogle Scholar
  218. 218.
    Iyer RK, Bowles PA, Kim H, Dulgar-tulloch A (2018) Industrializing autologous adoptive immunotherapies: manufacturing advances and challenges. Front Med 5:150Google Scholar
  219. 219.
    Peltzer J et al (2018) Mesenchymal stromal cells based therapy in systemic sclerosis: rational and challenges. Front Immunol 9:2013PubMedPubMedCentralGoogle Scholar
  220. 220.
    Coopman K, Medcalf N (2014) From production to patient: challenges and approaches for delivering cell therapies. In: StemBook.  https://doi.org/10.3824/STEMBOOK.1.97.1 CrossRefGoogle Scholar
  221. 221.
    Dhall S et al (2018) Properties of viable lyopreserved amnion are equivalent to viable cryopreserved amnion with the convenience of ambient storage. PLoS One 13:1–19Google Scholar
  222. 222.
    Paton J (2018) Novartis’ Kymriah cancer drug priced at 320,000 euros in Germany. BloombergGoogle Scholar
  223. 223.
    Hirschler B (2018) UK rejects Gilead’s CAR-T cancer cell therapy as too expensive. ReutersGoogle Scholar
  224. 224.
    Liu A (2018) Beat you to it, Kymriah: Gilead strikes discount Yescarta deal with NHS in adults. Fierce PharmaGoogle Scholar
  225. 225.
    National Institute for Health and Care Excellence (2019) Darvadstrocel for treating complex perianal fistulas in Crohn’s disease. LondonGoogle Scholar
  226. 226.
    Panés J et al (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388:1281–1290PubMedGoogle Scholar
  227. 227.
    Chilima TDP, Moncaubeig F, Farid SS (2018) Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement. Biochem Eng J 137:132–151Google Scholar
  228. 228.
    Trainor N, Pietak A, Smith T (2014) Rethinking clinical delivery of adult stem cell therapies. Nat Biotechnol 32:729–735Google Scholar
  229. 229.
    Torikai H et al (2012) A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119:5697–5705PubMedPubMedCentralGoogle Scholar
  230. 230.
    Jenkins MJ, Farid SS (2018) Cost-effective bioprocess design for the manufacture of allogeneic CAR-T cell therapies using a decisional tool with multi-attribute decision-making analysis. Biochem Eng J 137:192–204Google Scholar
  231. 231.
    Simaria AS et al (2014) Allogeneic cell therapy bioprocess economics and optimization: single-use cell expansion technologies. Biotechnol Bioeng 111:69–83PubMedGoogle Scholar
  232. 232.
    US Drug and Food Administration (2004) Pharmaceutical CGMPs for the 21st century – a risk-based approach. FDAGoogle Scholar
  233. 233.
    Rathore AS, Winkle H (2009) Quality by design for biopharmaceuticals. Nat Biotechnol 27:26–34PubMedGoogle Scholar
  234. 234.
    EMA & FDA (2017) Report from the EMA-FDA QbD pilot program (EMA/213746/2017)Google Scholar
  235. 235.
    Senior M (2017) After Glybera’s withdrawal, what’s next for gene therapy? Nat Biotechnol 35:491–492PubMedGoogle Scholar
  236. 236.
    Grover N (2014) Dendreon files for bankruptcy as cancer vaccine disappoints. ReutersGoogle Scholar
  237. 237.
    Lipsitz YY, Timmins NE, Zandstra PW (2016) Quality cell therapy manufacturing by design. Nat Biotechnol 34:393–400PubMedGoogle Scholar
  238. 238.
    Martin-Moe S et al (2011) A new roadmap for biopharmaceutical drug product development: integrating development, validation, and quality by design. J Pharm Sci 100:3031–3043PubMedGoogle Scholar
  239. 239.
    Rathore AS (2009) Roadmap for implementation of quality by design (QbD) for biotechnology products. Trends Biotechnol 27:546–553PubMedGoogle Scholar
  240. 240.
    Mandenius C-F et al (2009) Quality-by-design for biotechnology-related pharmaceuticals. Biotechnol J 4:600–609PubMedGoogle Scholar
  241. 241.
    Hunt MM, Meng G, Rancourt DE, Gates ID, Kallos MS (2013) Factorial experimental design for the culture of human embryonic stem cells as aggregates in stirred suspension bioreactors reveals the potential for interaction effects between bioprocess parameters. Tissue Eng Part C Methods 20:76–89PubMedGoogle Scholar
  242. 242.
    Ratcliffe E et al (2013) Application of response surface methodology to maximize the productivity of scalable automated human embryonic stem cell manufacture. Regen Med 8:39–48PubMedGoogle Scholar
  243. 243.
    Andrade PZ, Dos Santos F, Almeida-Porada G, Lobato Da Silva C, Joaquim JM (2010) Systematic delineation of optimal cytokine concentrations to expand hematopoietic stem/progenitor cells in co-culture with mesenchymal stem cells. Mol BioSyst 6:1207–1215PubMedGoogle Scholar
  244. 244.
    Csaszar E et al (2012) Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell 10:218–229PubMedGoogle Scholar
  245. 245.
    van Poll D et al (2008) Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology 47:1634–1643PubMedGoogle Scholar
  246. 246.
    Gnecchi M et al (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669PubMedGoogle Scholar
  247. 247.
    Teixeira FG et al (2016) Modulation of the mesenchymal stem cell secretome using computer-controlled bioreactors: impact on neuronal cell proliferation, survival and differentiation. Sci Rep 6:1–14Google Scholar
  248. 248.
    Mukherjee P, Mani S (2013) Methodologies to decipher the cell secretome. Biochim Biophys Acta Proteins Proteomics 1834:2226–2232Google Scholar
  249. 249.
    Paltridge JL, Belle L, Khew-Goodall Y (2013) The secretome in cancer progression. Biochim Biophys Acta Proteins Proteomics 1834:2233–2241Google Scholar
  250. 250.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172PubMedGoogle Scholar
  251. 251.
    Ratajczak J et al (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–856PubMedGoogle Scholar
  252. 252.
    Valadi H et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659Google Scholar
  253. 253.
    Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteome 73:1907–1920Google Scholar
  254. 254.
    Van Niel G, D’Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19:213–228Google Scholar
  255. 255.
    György B et al (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688PubMedPubMedCentralGoogle Scholar
  256. 256.
    Lopez-Verrilli MA, Picou F, Court FA (2013) Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61:1795–1806PubMedGoogle Scholar
  257. 257.
    Barile L et al (2014) Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 103:530–541PubMedGoogle Scholar
  258. 258.
    Peinado H et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891PubMedPubMedCentralGoogle Scholar
  259. 259.
    Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826PubMedPubMedCentralGoogle Scholar
  260. 260.
    Yan W et al (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol.  https://doi.org/10.1038/s41556-018-0083-6 PubMedPubMedCentralGoogle Scholar
  261. 261.
    Sharples RA et al (2008) Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J 22:1469–1478PubMedGoogle Scholar
  262. 262.
    Wiklander OPB et al (2015) Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4:1–13Google Scholar
  263. 263.
    Yang T et al (2015) Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res 32:2003–2014PubMedPubMedCentralGoogle Scholar
  264. 264.
    Lai RC et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222PubMedGoogle Scholar
  265. 265.
    Bruno S et al (2012) Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One 7:e33115PubMedPubMedCentralGoogle Scholar
  266. 266.
    Batrakova EV, Kim MS (2015) Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release 219:396–405PubMedPubMedCentralGoogle Scholar
  267. 267.
    Wang X et al (2018) Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction. J Am Heart Assoc 7:1–16Google Scholar
  268. 268.
    Alvarez-Erviti L et al (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345PubMedGoogle Scholar
  269. 269.
    Tian Y et al (2014) A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35:2383–2390PubMedGoogle Scholar
  270. 270.
    Kim MS et al (2016) Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 12:655–664PubMedGoogle Scholar
  271. 271.
    Li Y et al (2018) A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal cancer. Nanomedicine 14:1973–1985PubMedGoogle Scholar
  272. 272.
    Kim MS et al (2018) Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine 14:195–204PubMedGoogle Scholar
  273. 273.
    Colao IL, Corteling R, Bracewell D, Wall I (2018) Manufacturing exosomes: a promising therapeutic platform. Trends Mol Med 24:242–256PubMedGoogle Scholar
  274. 274.
    Vader P, Mol EA, Pasterkamp G, Schiffelers RM (2016) Extracellular vesicles for drug delivery. Adv Drug Deliv Rev 106:148–156PubMedGoogle Scholar
  275. 275.
    Conlan RS, Pisano S, Oliveira MI, Ferrari M, Mendes Pinto I (2017) Exosomes as reconfigurable therapeutic systems. Trends Mol Med 23:636–650PubMedPubMedCentralGoogle Scholar
  276. 276.
    Papadimitropoulos A et al (2014) Expansion of human mesenchymal stromal cells from fresh bone marrow in a 3D scaffold-based system under direct perfusion. PLoS One 9:e102359PubMedPubMedCentralGoogle Scholar
  277. 277.
    Hümmer C et al (2016) Automation of cellular therapy product manufacturing: results of a split validation comparing CD34 selection of peripheral blood stem cell apheresis product with a semi-manual vs. an automatic procedure. J Transl Med 14:1–7Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Miguel de Almeida Fuzeta
    • 1
  • André Dargen de Matos Branco
    • 1
  • Ana Fernandes-Platzgummer
    • 1
  • Cláudia Lobato da Silva
    • 1
    Email author
  • Joaquim M. S. Cabral
    • 1
  1. 1.Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior TécnicoUniversidade de LisboaLisboaPortugal

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